Medical References

Recent years have seen an explosion in the development and application of molecular tools for identifying microbes and analyzing their activity. These tools are increasingly applied to strains of lactic acid bacteria (LAB), including those used in fermentation and as well as those marketed as probiotics, for identification and analysis of their activity. Many of these tools are based on 16S ribosomal DNA sequences and exploit either hybridization or PCR techniques. Furthermore, complete or partial genomes of various LAB and bifidobacteria have been determined and offer omics-based approaches to analyze the activity of the bacteria provided that the mechanisms of their action are known. Finally, fluorescent probes coupled to flow cytometry are used to monitor the physiological capacity of bacterial cells in situ. All these approaches can be used for the screening and selection of LAB, assessing their role in fermentation and flavor development in fermented products. Additional aspects of probiotic LAB include their viability and vitality during processing and analysis of their presence, persistence, and performance in the gastrointestinal tract. An overview of these approaches is provided, and specific examples of their application to lactic cultures are presented. Because of their abundant use in tracing and tracking of LAB, a complete listing of 16S ribosomal RNA probes for lactobacilli and bifidobacteria is provided.

Lactic acid bacteria (LAB) are widely used for the industrial production of fermented dairy products and form a group of related low-GC-content gram-positive bacteria. The major species used in dairy manufacturing are Lactobacillus, Lactococcus, Streptococcus, and Leuconostoc. Traditionally most are applied as starter cultures for dairy fermentations or used as probiotic cultures, delivered in dairy vehicles. The appearance of the genomes of Lactococcus lactis, Bidifobacterium longum, Lactobacillus plantarum, L. johnsonii, L. acidophilus, 2 strains of Streptococcus thermophilus, and pending completion of many draft genomic sequences, is now promoting in-depth investigation into the comparative genetic content of LAB. Moreover, whole-genome transcriptional arrays are quickly revealing critical genes/operons that are coordinately expressed and the impact of environmental factors on expression of multiple gene sets. Comparative genomics between multiple genomes is providing insights into genes that are important in metabolic, physiological, and functional roles for different LAB in the environments they inhabit, ranging from the gastrointestinal tract to milk and acidified dairy products.

The bacteria colonizing the human intestinal tract exhibit a high phylogenetic diversity that reflects their immense metabolic potential. By virtue of their catalytic activity, the human gut micro-organisms have an impact on gastrointestinal function and host health. All dietary components that escape digestion in the small intestine are potential substrates of the bacteria in the colon. The bacterial conversion of carbohydrates, proteins and nonnutritive compounds such as polyphenolic substances leads to the formation of a large number of compounds that may have beneficial or adverse effects on human health.

Mucosal surfaces represent the main sites in which environmental microorganisms and antigens interact with the host. In particular the intestinal mucosal surfaces are in continuous contact with a heterogeneous population of microorganisms of the endogenous flora and are exposed to food and microbes. As a result, the immune system of the host has to discriminate between pathogenic and commensal microorganisms. This article reviews the types of sentinel cells that continuously sense the environment and coordinate immune defenses as well as the mechanisms of the innate and adaptive immune systems that are activated by bacterial and viral molecular patterns leading to inflammatory, allergic, or regulatory immune response with special emphasis on probiotic bacteria.

The immune system acts to protect the host from infectious agents that exist in the environment and from other noxious insults. It is constantly active, acting to discriminate "nonself" from "self." The immune system has 2 functional divisions: the innate and the acquired. Both involve various blood-borne factors and cells. A number of methodologies exist to assess aspects of immune function; many of these rely on studying cells in culture ex vivo. There are large interindividual variations in many immune functions even among the healthy. Many factors, including genetics, gender, age, nutrient status, and gut flora, contribute to the observed variation. Individuals with immune responses significantly below "normal" are more susceptible to infectious agents and exhibit increased infectious morbidity and mortality. However, it is not clear how the variation in immune function among healthy individuals relates to variation in susceptibility to infection.

Among the numerous purported health benefits attributed to probiotic bacteria, their capacity to interact with the immune system of the host is now supported by an increasing number of in vitro and in vivo experiments. In addition to these, a few well-controlled human intervention trials aimed at preventing chronic immune dysregulation have been reported. Even though the precise molecular mechanisms governing the cross-talk between these beneficial bacteria and the intestinal ecosystem remain to be discovered, a new and fascinating phase of research has been initiated in this area as demonstrated by a series of recent articles. This article summarizes the status and latest progress of the field in selected areas and aims at identifying key questions that remain to be addressed, especially concerning the translocation of ingested bacteria, the identification of major immunomodulatory compounds of probiotics, and specific aspects of the host-microbe cross-talk. The interaction with immunocompetent cells and the role of secretory IgA in gut homeostasis are also evoked. Finally, a brief overview is provided on the potential use of recombinant DNA technology to enhance the health benefits of probiotic strains and to unravel specific mechanisms of the host-microbe interaction.

Nine healthy middle-aged and 10 elderly volunteers drank fermented milk containing 4 x 1010 live cells of Lactobacillus casei strain Shirota daily for 3 wk, and their natural killer (NK) activity and other immunological functions were examined. In the experiments with middle-aged volunteers, NK activity significantly increased (P < 0.01) 3 wk after the start of intake, elevated NK cell activity remained for the next 3 wk, and this effect was particularly prominent in the low-NK-activity individuals. In the experiments with elderly volunteers, NK activity significantly decreased (P < 0.01) in the control group 3 wk after the start of intake; however, the intake of Lactobacillus casei strain Shirota maintained the NK activity. These results suggest that daily intake of Lactobacillus casei strain Shirota provides a positive effect on NK-cell activity.

A considerable part of the Western population suffers from some form of allergy, and the incidence is still rising with no sign of an end to this trend. Reduced exposure to microbial allergens as a result of our hygienic lifestyle has been suggested as one of the possible causes. It has also been suggested that probiotics may provide safe alternative microbial stimulation needed for the developing immune system in infants. This idea is supported by the fact that allergic infants have been observed to have an aberrant intestinal microbiota. They were shown to have more clostridia and fewer bifidobacteria and, in addition, to have an adult-like Bifidobacterium microbiota. Clinical trials have shown that the standard treatment of infants with atopic eczema, extensively hydrolyzed infant formula, can be significantly improved through the addition of Lactobacillus rhamnosus GG or Bifidobacterium lactis Bb-12. It has also been shown possible to halve the incidence of allergy in at-risk infants through administration of L. rhamnosus GG to expecting mothers and subsequently to their infants during the first half-year of life. Many mechanisms have been proposed for these beneficial effects, ranging from improved mucosal barrier function to direct influences on the immune system. However, the exact mode(s) of action are not yet known. For the future, elucidation of these mechanisms will be an important target. Another important area will be the investigation of interactions between probiotics and other food components that influence allergies. This will enable optimization of probiotic use for the allergic subject.

Lactobacillus casei strain Shirota (LcS) has been demonstrated to have beneficial effects in numerous murine disease models via host immune modulation. It has also been reported that LcS induced recovery of host immune responses that were decreased by treatment with carcinogens and augmented the natural killer activity and T-cell functions of host immune cells. After LcS is ingested by the host, it is incorporated into M cells in Peyer's patches (PP) and digested to form active components. In PP, macrophages or dendritic cells that phagocytosed LcS gained the ability to produce several cytokines, especially tumor necrosis factor-. The components of LcS digested in PP were then recognized through toll-like receptor 2 in antigen-presenting cells, resulting in the production of several cytokines that elicited varied responses in host immune cells. Also, it was observed by 2D-PAGE analyses that the expression level and/or the phosphorylation of some proteins in PP and mesenteric lymph nodes were definitely altered by the ingestion of LcS, providing more evidence of cellular responses. These results suggest that some probiotic bacteria have the potential to augment or modify the host immune function through the regulation of host immune cells.

Probiotics have preventive as well as curative effects on several types of diarrhea of different etiologies. Prevention and therapy (or alleviation) of diarrhea have been successfully investigated for numerous dietary probiotics to establish probiotic properties and to justify health claims (the medicinal use of probiotic food and the therapy of gastrointestinal diseases itself may not be advertised under current food laws). Other probiotic microorganisms (e.g., Lactobacillus rhamnosus GG, L. reuteri, certain strains of L. casei, L. acidophilus, Escherichia coli strain Nissle 1917, and certain bifidobacteria and enterococci (Enterococcus faecium SF68) as well as the probiotic yeast Saccharomyces boulardii have been investigated with regard to their medicinal use, either as single strains or in mixed-culture probiotics. However, the effects on humans have been assessed mainly in smaller (n < 100) randomized, controlled clinical studies or in open label trials, but large intervention studies and epidemiological investigations of long-term probiotic effects are largely missing. Perhaps with the exception of nosocomial diarrhea or antibiotic-associated diarrhea, the results of these studies are not yet sufficient to give specific recommendations for the clinical use of probiotics in the treatment of diarrhea.

Helicobacter pylori infection, a highly prevalent pathogen, is a major cause of chronic gastritis and peptic ulcer and a risk factor for gastric malignancies. Antibiotics-based H. pylori eradication treatment is 90% effective. However, it is expensive and causes side effects and antibiotic resistance. Probiotics could present a low-cost, large-scale alternative solution to prevent or decrease H. pylori colonization. A literature search of the MEDLINE database (1966–2006) has been performed selecting all in vitro, animal, and human fully published English-language studies dealing with H. pylori and probiotics. Probiotics had an in vitro inhibitory effect on H. pylori. Animal studies demonstrated that probiotic treatment is effective in reducing H. pylori–associated gastric inflammation. Seven of 9 human studies showed an improvement of H. pylori gastritis and decrease in H. pylori density after administration of probiotics. The addition of probiotics to standard antibiotic treatment improved H. pylori eradication rates (81% vs. 71%, with combination treatment vs. H. pylori–eradication treatment alone; 2test: P = 0.03). Probiotic treatment reduced H. pylori therapy-associated side effects (incidence of side effects: 23% vs. 46%, with combination therapy vs. H. pylori–eradication treatment alone; 2test: P = 0.04). No study could demonstrate the eradication of H. pylori infection by probiotic treatment. So long-term intake of products containing probiotic strains of probiotics may have a favorable effect on H. pylori infection in humans, particularly by reducing the risk of developing disorders associated with high degrees of gastric inflammation.

Components of the commensal flora, including Bifidobacteria and Lactobacilli, have been associated with beneficial effects on the host. These beneficial effects include maintenance of intestinal homeostasis, competitive exclusion of pathogens, production of antimicrobial compounds, promotion of gut barrier function, and immune modulation. Probiotics currently can be administered in dairy yogurts and drinks and also in the form of sachets or capsules. Although preliminary studies are clearly promising, placebo-controlled, randomized, double-blind clinical trials are required to clarify the role of probiotic bacteria in the treatment of inflammatory bowel disease. The choice of probiotic bacteria, the optimal dose, mode of administration, and duration of therapy still need to be established. Detailed strain characterization is also required for all potential probiotic strains. As evidence accumulates to suggest a breakdown in tolerance toward ubiquitous intestinal bacteria, it appears logical to intervene by modulating the enteric flora. Increasingly, research suggests that probiotics may offer an alternative or adjuvant approach to conventional therapy by altering the intestinal microflora and modulating the host immune system.

Epidemiological studies suggest that milk consumption and dietary intake of dairy proteins are inversely related to the risk for hypertension. Also, some intervention studies have shown a blood pressure-lowering effect of milk products and dairy proteins. Milk peptides are formed from milk proteins by enzymatic breakdown by digestive enzymes or by the proteinases formed by lactobacilli during the fermentation of milk. Several milk peptides have been shown to have antihypertensive effects in animal and in clinical studies. The most studied mechanism underlying the antihypertensive effects of milk peptides is inhibition of angiotensin-converting enzyme. Milk peptides may also have other additional mechanisms to lower blood pressure such as opioid-like activities and mineral-binding and antithrombotic properties. The future challenge is to identify the antihypertensive components in milk and their mechanisms of action and thus to find more possibilities for using these constituents and products as a dietary treatment of hypertension.

A prebiotic is "a selectively fermented ingredient that allows specific changes, both in the composition and/or activity in the gastrointestinal microflora that confers benefits upon host well-being and health." Today, only 2 dietary nondigestible oligosaccharides fulfill all the criteria for prebiotic classification. The daily dose of the prebiotic is not a determinant of the prebiotic effect, which is mainly influenced by the number of bifidobacteria/g in feces before supplementation of the diet with the prebiotic begins. The ingested prebiotic stimulates the whole indigenous population of bifidobacteria to growth, and the larger that population, the larger is the number of new bacterial cells appearing in feces. The "dose argument" is thus not supported by the scientific data: it is misleading for consumers and should not be allowed. A prebiotic index is proposed, defined as "the increase in the absolute number of bifidobacteria expressed divided by the daily dose of prebiotic ingested."

Several studies in animals and humans have shown positive effects of nondigestible oligosaccharides (NDO) on mineral absorption and metabolism and bone composition and architecture. These include inulin, oligofructose, fructooligosaccharides, galactooligosaccharides, soybean oligosaccharide, and also resistant starches, sugar alcohols, and difructose anhydride. A positive outcome of dietary prebiotics is promoted by a high dietary calcium content up to a threshold level and an optimum amount and composition of supplemented prebiotics. There might be an optimum composition of fructooligosaccharides with different chain lengths (synergy products). The efficacy of dietary prebiotics depends on chronological age, physiological age, menopausal status, and calcium absorption capacity. There is evidence for an independent probiotic effect on facilitating mineral absorption. Synbiotics, i.e., a combination of prebiotics and prebiotics, can induce additional effects. Whether a low content of habitual NDO would augment the effect of dietary prebiotics or synbiotics remains to be studied. The underlying mechanisms are manifold: increased solubility of minerals because of increased bacterial production of short-chain fatty acids, which is promoted by the greater supply of substrate; an enlargement of the absorption surface by promoting proliferation of enterocytes mediated by bacterial fermentation products, predominantly lactate and butyrate; increased expression of calcium-binding proteins; improvement of gut health; degradation of mineral complexing phytic acid; release of bone-modulating factors such as phytoestrogens from foods; stabilization of the intestinal flora and ecology, also in the presence of antibiotics; stabilization of the intestinal mucus; and impact of modulating growth factors such as polyamines. In conclusion, prebiotics are the most promising but also best investigated substances with respect to a bone-health-promoting potential, compared with probiotics and synbiotics. The results are more prominent in animal models, where more studies have been performed, than in human studies, where experimental conditions are more difficult to control.

Feeding infants breast milk of healthy mothers is associated with a lower incidence of infectious and allergic diseases. Although this effect is of multifactorial origin, it is widely accepted that the entire intestinal flora of breast-fed infants provides antiinfective properties and is an important stimulating factor for the postnatal development of the immune system. The effect of human milk on the postnatal development of the intestinal flora cannot be attributed to a single ingredient. It is generally accepted, however, that human milk oligosaccharides play a key role in this matter. Apart from their prebiotic effects, there is also evidence that human milk oligosaccharides act as receptor analogs to inhibit the adhesion of pathogens on the epithelial surface and interact directly with immune cells. Because of their complexity, oligosaccharides with structures identical to human milk oligosaccharides are not yet available as dietary ingredients. In the current search for alternatives, non-milk-derived oligosaccharides have gained much attention. As 1 example, a mixture of neutral galacto-oligosaccharides and long chain fructo-oligosaccharides have been identified as effective prebiotic ingredients during infancy. Furthermore, another class of oligosaccharides with a potential physiological benefit could be those found in animal milks. Most of the oligosaccharides detected in domestic animal milks have some structural features in common with human milk oligosaccharides. One important fact is the occurrence of sialic acids such as N-acetylneuraminic acids. However, total amounts and individual structures are still different from those in human milk oligosaccharides. Although these structural similarities between animal milk and human milk oligosaccharides are promising, further studies are needed to proove the equivalence of their function.

Following on from the FAO/WHO Expert Consultation and Working Group outputs on probiotics and their presentation to Codex, it is hoped that these will be used as a science-based risk assessment process for managerial decision on probiotics and that the "Guidelines for the Evaluation of Probiotics in Food" will be used as a model for scientific criteria for evaluation of health claims. It is also hoped that this work will be incorporated or taken as example for the Codex draft being prepared on health and nutrition claims and as a scientific assessment of a novel food and that the probiotic guidelines will be adopted by Industry.

Functional foods and ingredients that are safe and efficacious have the potential for a positive impact on health. Current regulations in the United States governing claims about foods and dietary supplements, including functional foods and ingredients, are briefly reviewed. Research and communications challenges necessary to bring such products to the market are discussed.

A food (ingredient) is regarded as functional if it is satisfactorily demonstrated to affect beneficially 1 or more target functions in the body beyond adequate nutritional effects. The term inulin-type fructans covers all ß(21) linear fructans including native inulin (DP 2–60, DPav = 12), oligofructose (DP 2–8, DPav = 4), and inulin HP (DP 10–60, DPav = 25) as well as Synergy 1, a specific combination of oligofructose and inulin HP. Inulin-type fructans resist digestion and function as dietary fiber improving bowel habits. But, unlike most dietary fibers, their colonic fermentation is selective, thus causing significant changes in the composition of the gut microflora with increased and reduced numbers of potentially health-promoting bacteria and potentially harmful species, respectively. Both oligofructose and inulin act in this way and thus are prebiotic: they also induce changes in the colonic epithelium and in miscellaneous colonic functions. In particular, the claim "inulin-type fructans enhance calcium and magnesium absorption" is scientifically substantiated, and the most active product is oligofructose-enriched inulin (Synergy 1). A series of studies furthermore demonstrate that inulin-type fructans modulate the secretion of gastrointestinal peptides involved in appetite regulation as well as lipid metabolism. Moreover, a large number of animal studies and preliminary human data show that inulin-type fructans reduce the risk of colon carcinogenesis and improve the management of inflammatory bowel diseases. Inulin-type fructans are thus functional food ingredients that are eligible for enhanced function claims, but, as more human data become available, risk reduction claims will become scientifically substantiated.

The human gut microbiota plays a significant role in human health through its ability to digest food ingredients and manufacture metabolites. This can be positive or negative for host welfare. Moreover, the microflora plays an active role in host defense whereby colonization resistance affords protection against pathogens. Prebiotics are nondigestible food ingredients that target beneficial components of the gut microflora (mainly colonic), particularly the bifidobacteria. In vitro and in vivo evidence has accumulated to confirm the prebiotic effects of inulin-derived fructans.

Osteoporosis is a debilitating disease that affects many older people. Fragility fractures are the hallmark of osteoporosis. Although nutrition is only 1 of many factors that influence bone mass and fragility fractures, there is an urgent need to develop and implement nutritional approaches and policies for the prevention and treatment of osteoporosis that could, with time, offer a foundation for population-based preventive strategies. However, to develop efficient and precocious strategies in the prevention of osteoporosis, it is important to determine which modifiable factors, especially nutritional factors, are able to improve bone health throughout life. There are potentially numerous nutrients and dietary components that can influence bone health, and these range from the macronutrients to micronutrients as well as bioactive food ingredients. The evidence-base to support the role of nutrients and food components in bone health ranges from very firm to scant, depending on the nutrient/component. This article initially overviews osteoporosis, including its definition, etiology, and incidence, and then provides some information on possible dietary strategies for optimizing bone health and preventing osteoporosis. The potential benefits of calcium, vitamin D, vitamin K1, phytoestrogens, and nondigestible oligosaccharides are briefly discussed, with particular emphasis on the evidence base for their benefits to bone. It also briefly considers some of the recent findings that highlight the importance of some dietary factors for bone health in childhood and adolescence.

Nondigestible oligosaccharides have been shown to increase the absorption of several minerals (calcium, magnesium, in some cases phosphorus) and trace elements (mainly copper, iron, zinc). Inulin-type fructans including oligofructose and fructooligosaccharides derived from sucrose by enzymatic transfructosylation are the best investigated food ingredients in this respect. The stimulation of absorption was more pronounced when the demand for calcium was high, i.e., in animals in the rapid growing stage and in animals with impaired calcium absorption because of either ovariectomy or gastrectomy. Even a small stimulation of calcium absorption increased the mineral accumulation in the skeleton because of its persisting effect over months. Inulin-type fructans stimulated mineral absorption and bone mineral accretion when combined with probiotic lactobacilli and in the presence of antibiotics. Direct comparison of different inulin-type fructans revealed a more pronounced effect by inulin or a mixture of long-chain inulin and oligofructose than by oligofructose alone. Mechanisms on how inulin-type fructans mediate this effect include acidification of the intestinal lumen by short-chain fatty acids increasing solubility of minerals in the gut, enlargement of the absorption surface, increased expression of calcium-binding proteins mainly in the large intestine, modulated expression of bone-relevant cytokines, suppression of bone resorption, increased bioavailability of phytoestrogens, and, via stimulation of beneficial commensal microorganisms, increase of calcium uptake by enterocytes. Under certain conditions, inulin-type fructans may improve mineral absorption by their impact on the amelioration of gut health including stabilization of the intestinal flora and reduction of inflammation. The abundance of reports indicate that inulin-type fructans are promising substances that could help to improve the supply with available calcium in human nutrition and by this contribute to bone health.

Calcium absorption and whole-body bone mineral content are greater in young adolescents who receive 8 g/d of Synergy, a mixture of inulin-type fructans (ITF), compared with those who received a maltodextrin control. Not all adolescents responded to this intervention, however. We evaluated 32 responders and 16 nonresponders to the calcium absorptive benefits of ITF. We found no differences in usual dietary calcium intakes. Responders who increased their calcium absorption by at least 3% after 8 wk of Synergy had a greater accretion of calcium to the skeleton over a year based on whole-body dual-energy x-ray absorptiometry data. The absorptive benefit to ITF use in responders is substantial and would be comparable to increasing daily calcium intake by at least 250 mg. Increased intake of ITF may be an important aspect of a multifaceted approach to enhancing peak bone mass.

In humans, there is increasing evidence that the colon can absorb nutritionally significant amounts of calcium, and this process may be susceptible to dietary manipulation by fermentable substrates, especially inulin-type fructans. Inulin-type fructans can modulate calcium absorption because they are resistant to hydrolysis by mammalian enzymes and are fermented in the large intestine to produce short-chain fatty acids, which in turn reduce luminal pH and modify calcium speciation, and hence solubility, or exert a direct effect on the mucosal transport pathway. Quite a few intervention studies showed an improvement of calcium absorption in adolescents or young adults by inulin-type fructans. In the same way, a positive effect has been reported in older women.

A growing body of evidence demonstrates the role of gut-derived hormones in the control of energy homeostasis. Among those intestinal signals, physiological and therapeutic interest has been drawn to glucagon-like peptide-1 (GLP-1). The main reasons are that this hormone 1) is secreted by epithelial intestinal L-cells in response to glucose and lipids, 2) enhances glucose-stimulated insulin secretion, 3) improves blood glucose profiles of type 2 diabetic patients by means of several actions on pancreatic hormone secretions, 4) reduces body weight and food intake, and 5) slows gastric emptying. Furthermore, recent evidence has suggested that the nervous system is a key player accounting for the beneficial role of GLP-1 on the control of energy homeostasis. Hence, the role of GLP-1 on the gut-to-brain axis is reviewed.

There is a history of interest in the metabolic effects of alterations in small intestinal digestion and colonic fermentation of carbohydrate. It is believed that the rate of digestion of carbohydrate determines the place and form in which carbohydrate is absorbed. Slowly absorbed or lente carbohydrate sources may reduce postprandial glucose surges and the need for insulin with important implications for lowering coronary heart disease risk and reducing diabetes incidence. Carbohydrates that are not digested in the small intestine will enter the colon, and those that are fermentable will be salvaged as short-chain fatty acids in the colon and at the same time may stimulate colonic microflora, such as bifidobacteria. This process may have metabolic effects in the gut and throughout the host, possibly related to short-chain fatty acid products, although these effects are less well documented. One important aspect of colonic fermentation is the stimulation of certain populations of the colonic microflora, which may assist in the biotransformation of bioactive food components including the cleaving of plant phenolics from their glycone to produce the more rapidly absorbed aglycone. However, human studies have been limited. Therefore, further studies are required to explore these important aspects of metabolism related to the rate of carbohydrate absorption and fermentation and their implications in health and disease.

Inulin-type fructans have been tested for their capacity to modulate lipid and glucose metabolism in several animal models. Oligofructose (OFS) decreases food intake, fat mass development, and hepatic steatosis in normal and in obese rats; moreover, it exerts an antidiabetic effect in streptozotocin-treated rats and high-fat-fed mice. In most cases, the beneficial effects of OFS are linked to an increase of glucagon-like peptide-1 (GLP-1) level in the portal vein and of GLP-1 and proglucagon mRNA, its precursor, in the proximal colon. In this organ, OFS increases the number of GLP-1-positive L cells by promoting factors (Neurogenin 3 and NeuroD) involved in the differentiation of stem cells into L cells. The chronic administration of GLP-1 receptor antagonist exendin 9–39 totally prevents the beneficial effects of OFS (improved glucose tolerance, fasting blood glucose, glucose-stimulated insulin secretion, insulin-sensitive hepatic glucose production, and reduced body weight gain). Furthermore GLP-1 receptor knockout mice are completely insensitive to the antidiabetic actions of OFS. These findings highlight the potential interest of enhancing endogenous GLP-1 secretion by inulin-type fructans for the prevention/treatment of obesity and type 2 diabetes. Moreover, OFS is also able to modulate other gastrointestinal peptides (such as PYY and ghrelin) that could be involved in the control of food intake. Several studies in humans already support interest in OFS in the control of satiety, triglyceridemia, or steatohepatitis. The link with gut peptides production in humans remains to be proven.

Convincing evidence indicates that the intake of inulin-type fructans, inulin and oligofructose, has beneficial effects on blood lipid changes in animals, although data in humans have been considered contradictory. We conducted a meta-analysis of available literature to quantify the effects in humans of dietary inulin-type fructans on serum triacylglycerols. Fifteen eligible randomized, controlled trials published from 1995 to 2005, for a total of 16 comparisons, were identified from the PubMed (National Library of Medicine, Bethesda, MD) and SCOPUS (Elsevier B.V., Amsterdam, NL) databases. Standardized mean effect sizes were calculated for net changes in serum triacylglycerol concentrations using random-effect model. The intake of inulin-type fructans was associated with significant decreases in serum triacylglycerols by 0.17 mmol/L (95%CI –0.33, –0.01; Z = 2.12, P = 0.04) or 7.5%. Given the limited number of studies, no specific effects for gender, amount fed, duration of the study, background diet, overweight, hyperlipidemia, or diabetes were further formally investigated, but, from the test for heterogeneity [2 = 13.34, df = 15, (P = 0.55), I2 = 0%], it appears that the effect of inulin-type fructans on circulating triacylglycerols is consistent across conditions. In conclusion, dietary inulin-type fructans significantly reduced serum triacylglycerols. The mechanisms, possibly related to colonic fermentation and/or incretin release from the distal gut, warrant further studies.

Changes in diet greatly affect the mucosal immune system, particularly in diseases such as Crohn's disease and necrotizing enterocolitis. This article examines the hypothesis that alterations in the luminal environment of the intestine regulate the expression of genes in the enterocyte responsible for signaling to immune cells. Genes expressed by the epithelium orchestrate leukocytes in the lamina propria. For example, chemokine expression in the mouse intestinal epithelium, through transgenic means, induced the recruitment of neutrophils and lymphocytes into intestinal tissues. Diet alters the expression of the genes responsible for signaling by a variety of pathways. The introduction of a normal diet to a weanling mouse up-regulates MHC class II expression through a particular isoform of the class II transactivator, a protein that acts in the nucleus. SCFA concentrations in the intestinal lumen vary markedly with diet. SCFAs increase IL-8 and insulin-like growth factor binding protein-2 expression by inhibiting histone deacetylase activity in the enterocyte. Down-regulation of gene expression by butyrate can act through acetylation of the inhibitory transcription factor Sp3. The review therefore describes a number of molecular pathways, explaining how changes in diet may alter leukocyte recruitment by regulating enterocyte gene expression. Myofibroblasts enhance enterocyte chemotactic activity by cleaving inactive precursors; and myofibroblast genes also are regulated by SCFA. It is likely that other similar regulatory mechanisms remain to be discovered.

Diet modulates immune functions in different ways and affects host resistance to infections. In addition to the essential nutrients in food, nonessential food constituents such as nondigestible carbohydrates also affect the immune system. First results from human intervention studies suggest that the intake of inulin (IN) and oligofructose (OF) has beneficial effects on the gut-associated lymphoid tissue. At the level of the systemic immune system, however, only minor effects have been observed in healthy adult human subjects. In contrast, data from studies with infants suggest that supplementation with a prebiotic mixture positively affects postnatal immune development and increases fecal secretory IgA. Animal studies confirm the observations from human trials and give more insight into the immune tissue- specific effects of IN/OF. A clear outcome of the animal studies is that the intestinal immune system and especially the immune cells associated with the Peyer's patches are responsive to a dietary supplement of IN/OF and/or their metabolites. The mechanisms of IN/OF include indirect effects such as a shift in the composition of the intestinal flora and the enhanced production of immunoregulatory SCFA and perhaps other bacterial metabolites. Few data suggest direct effects of IN/OF via carbohydrate receptors on intestinal epithelial cells and immune cells. In conclusion, prebiotic IN/OF clearly modulate immunological processes at the level of the gut-associated lymphoid tissue, which may be associated with significant health benefits in infants and patients with inte